Buprenorphine is a semi-synthetic opioid analgesic with mixed agonist-antagonist properties. Besides being 20-40 times more potent than morphine, one of its main advantages is that the dose does not need to be increased during chronic administration. Buprenorphine can be in various forms such as sublingual tablets (0.2 mg) for the treatment of moderate, severe acute, and chronic pain, or as a pre-operative medication. Sublingual tablets containing 0.4, 2 and 8 mg of the drug are used for the treatment of opioid addiction. Alternatively, it is available as an injection (0.3 mg/mL) for intravenous (hereinafter, “IV”), intramuscular (hereinafter, “IM”), intrathecal, and epidural administration as an analgesia in cases of severe acute pain and as a pre-medication. Recommended doses are 200-600 μg by IV or IM injection every six to eight hours, 30-45 μg intrathecally or 100-300 μg epidurally every six to twelve hours or 400 μg sublingually every six to eight hours (R. C. Heel, R. N. Brogden, T. M. Speight and G. S. Avery, Drugs 17 (1979) 81-110; S. E. Robinson, CNS Drug Rev. 8 (2000) 377; P. J. Hoskin, G. W. Hanks, Drugs 30 (1991) 326; T. M. Tzschentke, Psychopharmacology 161 (2002) 1).
The prior art includes various references disclosing injectable slow-release formulations. For example, U.S. Pat. No. 6,495,155 discloses an injectable slow-release partial opioid agonist and/or opioid antagonist formulation in a poly (D, L-lactide) excipient with a small amount of residual ethyl acetate. The microparticles are under 125 μm in diameter and can be readily injected intramuscularly to provide at least about 0.5 ng/ml of drug over an extended period of time (28-60 days). The formulations are provided for use in the treatment of alcoholics and heroin addicts. Additionally, a subcutaneous depot product (Norvex™) exists wherein buprenorphine microcapsules consisting of buprenorphine base and biodegradable PLA-PGA polymer are disclosed (B. -F. X. Sobel et al. Drug and Alcohol Dependence 73 (2004) 11). Moreover, there are buprenorphine transdermal delivery systems (TDS) (e.g., Transtec™), formulated as a matrix patch and licensed for the treatment of moderate to severe cancer pain and severe pain not responding to non-opioid analgesics. The patch is available in three strengths delivering 35, 52.5 or 70 mcg/hr over seventy-two hours (R. Sittl et al., Clin. Ther. 2003 January; 25(1): 150; Expert Rev. Neurother. 2005 May; 5(3): 315).
A study has found that buprenorphine propionate when prepared as a depot had a long-lasting analgesic effect, which was 7.5-fold longer than the traditional dosage form of buprenorphine in saline preparation, following IM injection in rats. The long lasting effect of IM depot of buprenorphine propionate is reported to be due to a slow release of buprenorphine propionate from its oil vehicle (S. -Y. Liu et al., J. Chromatogr B 818 (2005) 233; J. J. Wang, Patent of the Republic of China, No. 1226830 (2005)). They have subsequently synthesized and formulated other depots of buprenorphine esters, buprenorphine enanthate and decanoate. The buprenorphine decanoate in oil produced a 14-fold longer duration of action than buprenorphine HCl in saline (K. -S. Liu et. al. Anesth Analg 2006; 102; 1445).
U.S. Pat. No. 6,335,035 discloses the preparation of a sustained release delivery system using a polymer matrix containing a drug for use in treating acute or chronic conditions. The drug is dispersed within a polymer matrix solubilized or suspended in a polymer matrix. The polymer matrix is composed of a highly negative charged polymer material such as polysulfated glucosoglycans, glycosaminoglycans, mucopolysaccharides and mixtures thereof, and a nonionic polymer such as carboxymethylcellulose sodium, hydroxyethyl cellulose, hydroxypropyl cellulose, and mixtures thereof.
U.S. Pat. No. 4,613,505 discloses a fat emulsion specific to an ester of flurbiprofen to provide an orally and parenterally administrable, particularly intravenously administrable, preparation having an excellent anti-inflammatory, analgesic and antipyretic activity and only a minor side effect.
U.S. Pat. No. 6,197,344 discloses controlled release suspension formulations of the opioid analgesic, butorphanol and the use of such formulations for pain management over periods of time ranging from 12 to 24 hours. South African Patent Application 91/4549 is referenced, which discloses microsphere pharmaceutical formulations and the use of such in delivering therapeutic agents. Pharmaceutically active substances that can be administered using such microspheres are tranquilizers, anti-emetics, vasodilators, antihistaminics, steroids and analgesics.
Finally, slow release emulsions containing either morphine base or morphine hydrochloride were prepared and formulated by Collier et. al. The preparation consists of suspending 150 mg of morphine base in 0.75 mL of an emulsifying agent, mannide monooleate (“Aracel A”), and 4.25 mL of light liquid paraffin. This oily phase was emulsified with 5 mL of 0.9% w/v NaCl in water (H. O. J. Collier et. al., Nature Vol 237 May 26, 1972).
Although the use of emulsions and suspensions for drug delivery is not uncommon and has been used in other analgesics, there are also problems associated with them. However, sustained release injectable buprenorphine formulations that exist in the prior art utilize more complicated systems such as microparticles or prodrugs in an oil vehicle. More particularly, the manufacturing of microparticles involves utilizing complex and costly processes with the use of organic solvents. Additionally, it can be difficult to achieve sterility of microparticles and other oil solutions because terminal sterilization is not always possible. In addition to these disadvantages, it is difficult to appropriately control the release of a drug such as buprenorphine in an injectable dosage form in order to achieve the desired onset and duration of analgesic effects in the target species. Accordingly, there continues to be a need for reasonably simpler and more practical formulations for sustained release of buprenorphine.